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Drug‑tolerant persister cells represent a major barrier to durable responses in cases of epidermal growth factor receptor (EGFR)‑mutant lung adenocarcinoma treated with tyrosine kinase inhibitors. To define the molecular features and actionable vulnerabilities of this cell state, public transcriptomic datasets from tumour cell‑based models treated with EGFR inhibitors or other targeted agents within the receptor tyrosine kinase (RTK)/RAS/MAPK pathway were integrated with machine‑learning‑based feature selection, survival analysis and Cancer Dependency Map‑based pharmacogenomic screening. The present study also performed experimental validation of identified genes and drugs in PC‑9 and HCC827 cell models. A four‑gene persister‑associated gene signature comprising B‑cell translocation gene 1 protein, inhibitor of growth protein 4, proline‑rich nuclear receptor coactivator 1 and calcium‑binding and coiled‑coil domain‑containing protein 1 was identified, which defined a targeted therapy‑induced persister state and associated with poor patient survival. Functional validation using reverse transcription‑quantitative PCR, doxycycline‑inducible short hairpin RNA knockdown and β‑galactosidase staining assays demonstrated rapid induction of these genes during osimertinib treatment and showed that depletion of each gene markedly impaired drug‑tolerant persister cell formation. Pharmacogenomic analysis identified ZLN005, a peroxisome proliferator‑activated receptor γ coactivator‑1α agonist, as a candidate metabolic modulator that synergized with osimertinib to reduce persister cell viability. Mechanistically, ZLN005 enhanced mitochondrial oxidative metabolism and reactive oxygen species accumulation, leading to caspase‑3 activation and gasdermin E‑associated pyroptotic cell death. Collectively, these findings defined the transcriptional and metabolic features of targeted therapy‑induced persister cells and revealed a metabolic vulnerability to ZLN005 in EGFR‑mutant lung adenocarcinoma.